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Malignancies of the Haemapoietic Stem Cell

Malignancies of the Haemapoietic Stem Cell. Haemapoietic Stem Cell are pluripotent and give rise to all of the haemopoietic cell under the action of cytokines. Stem cell are identified by CD34 positivity and CD117 positivity . CD117 is the receptor for stem cell factor .

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Malignancies of the Haemapoietic Stem Cell

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  1. Malignancies of the Haemapoietic Stem Cell

  2. Haemapoietic Stem Cell are pluripotent and give rise to all of the haemopoietic cell under the action of cytokines. • Stem cell are identified by CD34 positivity and CD117 positivity . CD117 is the receptor for stem cell factor

  3. Myeloproliferative Disorders • Chronic Myeloid Leukemia Ph’ chromosome • PolycythaemiaRubra Vera Jak-2 mutation V617F 95% Jak-2 exon 12 mutations (6) 3% • Essential Thrombocythaemia Jak-2 mutation 50% CALR mutation 40% c-mpl mutation 5% • Primary Myelofibrosis Jak-2 mutation 50%

  4. Myelodysplastic Disorders Abnormal looking haemopoitic cells with < 20% blasts in marrow • Refractory cytopaenia with unilineagedysplasia • Refractory cytopaenias with multilineagedysplasias • Refractory anaemia with ringed sideroblasts • Refractory anaemia with excess of blasts.

  5. High Risk MDS • Refractory Anaemia with Excess of Blasts • Secondary MDS from previous chemotherapy • Bad cytogenetics : p53 deletion Chr 17p Complex cytogenetics >/= 3 abnormalities

  6. Myelodysplastic/ myeloproliferative disorders • Chronic myelomonocytic leukemia • Juvenile myelomoncytic leukemia. • Atypical CML • Myelodysplastic/myeloproliferative disorders unclassified • RARS with marked thrombocytosis

  7. Chronic Myeloid Leukemia • Chronic phase • Accelerated Phase • Acute Leukemia within 5 years.

  8. Treatment • Alkylating agents • Interferon-alpha • Allogenic bone marrow transplant • Tyrosine Kinase inhibitors since 2003 Imatinib (Glivec) Dasatinib and nilotinib

  9. sss

  10. Acute leukemias • Children 70% ALL 30% AML • Adults 70% AML 20% ALL 10% Mixed Lineage

  11. AML • 1970’s French American British (FAB) • Morphology and Cytochemistry • Myeloperoxidase (MPO) +veMyeloblasts • Alpha-Napthyl Acetate Esterase +ve for Monoblasts • M1 Immature myeloblasts • M2 Some mature granulocytes • M3 Acute PromyelocyticLeukemia • M4 Acute MyelomonocyticLeukemia • M5 Acute MonocyticLeukemia • M6 Erytholeukemia • M7 MegakaryoblasticLeukemia • M0 in 1988 : MPO –ve but myeloid marker CD13, CD33 positive by flow cytometry

  12. M0 M1 M2 M3 M4 M5 M6 M7

  13. AML Recurrent Cytogenetic Abnormalities • M2 with t(8;21) RUNX1-RUNX1T1 • M4 Eos inv 16 (p13.q22) CBFB-MYH11 • M3 t(15;17) PML-RARA • M4/M5 t(9;11) MLLT3-MLL • AML with dysplasia t(6;9) • AML with thrombocytosis inv(3)(q21;q26.2) • M7 t(1,22)

  14. Acute PromyelocytcicLeukemia • Prone to DIC • Responds to All-trans retinoic Acid ATRA • Responds to low dose Arsenic

  15. ALL Recurrent cytogenetic abnormalities • B ALL t(9:22) t(12;21) TEL-AML1 or ETV6-RUNX1 t(1;19) t(v;11q23) MLL gene rearranged

  16. Gene mutation studies • FLT-3 (Fms like tyrosine kinase-3) • CEBPA (CCAAT enhancer-binder protein alpha) • NM1 (Nucleophosmin) • RUNX • WT1 • BAALC • ERG • MN1

  17. Treatment • Induction therapies • ALL Vincristine, Dexamethasone, L-asparaginase • AML Daunorubacin 3 days, Arabinoside-C 7 days • Bone marrow transplant for high risk patients and relapsed patients

  18. Novel Agents • Gemtuzamab Anti- CD33 • Farnesyltransferase inhibitors • Hypomethylating agents GPC islands to activate tumour suppressor genes.

  19. Genomics • Human Genome Project 1990-2003 • $3 billion dollars • Multiple institutions China, France, Germany, Japan, Spain, Uk, USA

  20. 25,000 genes. • 1.5% of genome are coding genes. 1% regulatory genes 97% non-coding sequences.

  21. New Generation Sequencers • Whole genome sequencing $1,000 - $5,000 In a little over 24 hrs

  22. Tumours studied • Acute leukemias • Bladder • Breast • Hepatocellular carcinoma • Eosophageal • Gastric • Pancreatic • Prostate

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